This application is the 371 of PCT/EP99/06139, filed on Aug. 21, 1999.
The invention relates to novel benzonaphthyridine N-oxides which are used in the pharmaceutical industry for the production of medicaments.
DE-A 21 23 328 and U.S. Pat. 3,899,494 describe substituted benzonaphthyridines which are distinguished by marked inhibition of blood platelet aggregation. International Applications WO 91/17991 and WO 98/121208 disclose 6-phenylbenzonaphthyridines for the treatment of inflammatory airway disorders.
It has now been found that the following compounds of the formula I which are described in greater detail and differ from the compounds of WO 91/17991 and WO 98/21208, in particular, by the substitution on the 6-phenyl ring and the presence of an N-oxide in the 2-position, have surprising and particularly advantageous properties.
The invention thus relates to compounds of the formula I 
in which
R1 is 1-4C-alkyl,
R2 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-4C-alkoxy which completely or predominantly substituted by fluorine,
R3 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-4C-alkoxy which completely or predominantly substituted by fluorine,
or in which
R2 and R3 together are a 1-2C-alkylenedioxy group,
R4 is a phenyl radical which is substituted by R5, where
R5 is a tetrazol-5-yl radical which is substituted by a radical R6, where
R6 is hydrogen, 1-10C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl or Ar-1-4C-alkyl,
xe2x80x83where
Ar is a phenyl radical which is unsubstituted or substituted by R7 and/or R8, and
R7 and R8 independently of one another are 1-4C-alkyl or 1-4C-alkoxy, and to the salts of these compounds.
1-4C-Alkyl represents a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl and, preferably, the ethyl and methyl radicals.
1-4C-Alkoxy represents radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and, preferably, the ethoxy and methoxy radicals.
3-7C-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
3-7C-Cycloalkylmethoxy represents cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy and cycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy are preferred.
As 1-4C-Alkoxy which is completely or predominantly substituted by fluorine, the 2,2,3,3,3-penta-fluoropropoxy, the perfluoroethoxy, the 1,2,2-trifluoroethoxy, in particular the 1,1,2,2-tetrafluoroethoxy, the trifluoromethoxy, the 2,2,2-trifluoroethoxy, and preferably the difluoromethoxy radicals, for example, may be mentioned.
1-2C-Alkylenedioxy represents, for example, the methylenedioxy (xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94) or the ethylenedioxy radical (xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94).
1-10C-Alkyl represents straight-chain or branched alkyl radicals having 1 to 10 carbon atoms. Examples which may be mentioned are the decyl, nonyl, octyl, heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl (3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
3-7C-Cycloalkyl represents the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl radical. The 5-7C-cycloalkyl radicals cyclopentyl, cyclohexyl and cycloheptyl may preferably be mentioned.
3-7C-Cycloalkylmethyl represents a methyl radical which is substituted by one of the abovementioned 3-7C-cycloalkyl radicals. Examples which may be mentioned are the cyclopentylmethyl and cyclohexyl-methyl radicals.
Ar-1-4C-alkyl is one of the abovementioned 1-4C-alkyl radicals which is substituted by one of the aryl radicals defined above. Examples which may be mentioned are the p-methoxybenzyl, the phenethyl and the benzyl radicals.
Suitable salts of compounds of the formula Ixe2x80x94depending on substitutionxe2x80x94are all acid addition salts or all salts with bases. The pharmacologically tolerable salts of the inorganic and organic acids and bases customarily used in pharmacy may be particularly mentioned. Those suitable are, on the one hand, water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxylbenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxyl-2-naphthoic acid, where the acids are employed in salt preparationxe2x80x94depending on whether a mono- or polybasic acid is concerned and depending on which salt is desiredxe2x80x94in an equimolar quantitative ratio or one differing therefrom.
On the other handxe2x80x94for example in the case of 1H- or 2H-tetrazol-5-yl substitutionxe2x80x94salts with bases are also suitable. Examples of salts with bases which may be mentioned are alkali metal (lithium, sodium, potassium) or calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidinium salts, where here too the bases are employed in salt preparation in an equimolar quantitative ratio or one differing therefrom.
Pharmacologically intolerable salts which can be obtained first, for example, as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically tolerable salts by methods known to the person skilled in the art.
It is known to the person skilled in the art that the compounds according to the invention and their salts, if they are isolated, for example, in crystalline form, can contain various amounts of solvents. The invention therefore also comprises all solvates and in particular all hydrates of the compounds of the formula I, and also all solvates in particular all hydrates of the salts of the compounds of the formula I.
Compounds of the formula I to be emphasized are those in which
R1 is 1-2C-alkyl,
R2 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R3 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
or in which
R2 and R3 together are a 1-2C-alkylenedioxy group,
R4 is a phenyl radical which is substituted by R5, where
R5 is a tetrazol-5-yl radical which is substituted by a radical R6, where
R6 is hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl or Ar-1-4C-alkyl,
xe2x80x83where
Ar is a phenyl radical which is unsubstituted or substituted by R7 and/or R8, and
R7 and R8 independently of one another are 1-4C-alkyl or 1-4C-alkoxy,
and the salts of these compounds.
Compounds of the formula I particularly to be emphasized are those in which
R1 is methyl,
R2 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-2C-alkoxy which is completely or predominantly substituted by fluorine,
R3 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-2C-alkoxy which is completely or predominantly substituted by fluorine,
R4 is a phenyl radical which is substituted by R5, where
R5 is a tetrazol-5-yl radical which is substituted by a radical R6, where
R6 is hydrogen, 1-7C-alkyl, 5-7C-cycloalkyl, 3-7C-cycloalkylmethyl or Ar-1-2C-alkyl,
xe2x80x83where
Ar is a phenyl radical which is unsubstituted or substituted by R7, and
R7 is 1-2C-alkyl or 1-2C-alkoxy,
and the salts of these compounds.
Preferred compounds of the formula I are those in which
R1 is methyl,
R2 is 1-4C-alkoxy,
R3 is 1-4C-alkoxy,
R4 is a phenyl radical which is substituted by R5, where
R5 is a tetrazol-5-yl radical substituted by a radical R6, where
R6 is hydrogen, 1-7C-alkyl, cyclohexylmethyl or 4-methoxybenzyl,
and the salts of these compounds.
Particularly preferred compounds of the formula I are those in which
R1 is methyl,
R2 is ethoxy,
R3 is methoxy or ethoxy,
R4 is a phenyl radical which is substituted by R5, where
R5 is a tetrazol-5-yl radical substituted by a radical R6, where
R6 is 1-4C-alkyl,
and the salts of these compounds.
The compounds of the formula I are chiral compounds having chiral centers in positions 2, 4a and 10b. The numbering of the compounds of the formula I is shown in formula Ia. 
The invention therefore relates to all eight conceivable enantiomers in any desired mixing ratio to one another. The compounds of the formula I are preferred in which the hydrogen atoms in positions 4a and 10b are in the cis position relative to one another.
Particularly preferred in this connection are those compounds of the formula I which in positions 4a and 10b have the same absolute configuration as the compound (xe2x88x92)-cis-4-amino-3-(3-ethoxy-4-methoxyphenyl)-1-methylpiperidine dihydrochloride having the optical rotation [xcex1]D20=xe2x88x9265.5xc2x0 (c=1, methanol) which can be employed as a starting material.
The tetrazol-5-yl radical R5 of the compounds of the formula I can be bonded to the phenyl radical R4 in the ortho, meta and also in the para position to the benzonaphthyridine ring.
Preferred compounds of the formula I are those in which the tetrazol-5-yl radical R5 is bonded to the phenyl radical R4 in the meta or para position to the benzonaphthyridine ring. Particularly preferred compounds of the formula I in this connection are those in which the tetrazol-5-yl radical R5 is bonded in the para position.
Compounds of the formula I in which R1, R2, R3, R4 and R5 have the meanings indicated above and R6 is hydrogen occur in a number of tautomeric forms, which are in equilibrium with one another (e.g. the 1H and 2H form of the tetrazol-5-yl radical). The invention comprises all tautomeric forms in any mixing ratio.
By bonding of the substituent R6 (R6xe2x89xa0H) to the tetrazol-5-yl group, the conversion of the two tautomeric 1H and 2H forms of the tetrazol-5-yl radical into one another is blocked. The invention therefore also relates to 1 H- and 2H-tetrazol-5-yl compounds of the formula I substituted by a radical R6 (R6xe2x89xa0H), both in pure form and in any mixing ratio. Preferred compounds of the formula I, however, are those in which the tetrazol-5-yl radical in the 2 position is substituted by one of the radicals R6 (R6xe2x89xa0H).
The invention further relates to a process for the preparation of the compounds of the formula I, in which R1, R2, R3 and R4 have the meanings indicated above, and their salts. The process comprises subjecting compounds of the formula II 
in which R1, R2, R3 and R4 have the meanings indicated above, to an N-oxidation reaction and, if desired, then converting the compounds of the formula I obtained into their salts, or, if desired, then converting salts of the compounds of the formula I obtained into the free compounds.
The N-oxidation is carried out in a manner familiar to the person skilled in the art, e.g. with the aid of hydrogen peroxide in methanol or with the aid of m-chloroperoxybenzoic acid in dichloromethane at room temperature. The person skilled in the art is familiar on the basis of his/her expert knowledge with the reaction conditions which are specifically necessary for carrying out the process.
Compounds of the formula II in which R1, R2 and R3 have the meanings indicated above, R4 is a phenyl radical substituted by a 1H- or 2H-tetrazol-5-yl radical R5, can be prepared, for example, from the corresponding compounds of the formula II in which R4 is a phenyl radical substituted by a cyano group, by reaction with an alkali metal azide and an ammonium halide (e.g. ammonium chloride). Corresponding reactions are described, for example, in J. Med. Chem. 1993, 36, 3246.
The compounds of the formula II obtained in this way can be converted into further compounds of the formula II, if desired, by an alkylation reaction, the hydrogen on the tetrazol-5-yl radical being replaced by one of the radicals mentioned above for R6 xe2x80x94excluding hydrogen.
The alkylation reactions are expediently carried out analogously to the methods known to the person skilled in the art, e.g. by reaction of the 1H- or 2H-tetrazol compounds of the formula II with compounds of the formula R6-X in the presence of a base, R6 having the abovementioned meaningsxe2x80x94excluding hydrogenxe2x80x94and X being a suitable leaving group such as a chlorine, bromine or iodine atom or an alkylsulfate radical. The 1- and 2-substituted tetrazole regioisomer mixtures usually formed in the alkylation are separated by methods known to the person skilled in the art, such as crystallization or chromatography on suitable support materials. An analogous alkylation of tetrazoles and separation of the regioisomers is described, for example, in J. Med. Chem. 1996, 39, 2354.
Compounds of the formula II in which R1, R2 and R3 have the meanings indicated above and R4 is a phenyl radical substituted by a tetrazol-5-yl radical R5, the tetrazol-5-yl radical R5, for its part, being substituted by R6 (R6xe2x89xa0hydrogen), can alternatively also be obtained by a cyclocondensation reaction of the corresponding compounds of the formula III 
The cyclocondensation is carried out in a manner known per se to the person skilled in the art according to Bischler-Napieralski (e.g. as described in J. Chem. Soc., 1956, 4280-4282) in the presence of a suitable condensing agent, such as, for example, polyphosphoric acid, phosphorus pentachloride, phosphorus trichloride, phosphorus pentoxide, thionyl chloride or preferably phosphorus oxytrichloride, in a suitable inert solvent, e.g. in a chlorinated hydrocarbon such as chloroform, or in a cyclic hydrocarbon such as toluene or xylene, or another inert solvent such as acetonitrile, or without a further solvent using an excess of condensing agent, preferably at elevated temperature, in particular at the boiling temperature of the solvent or condensing agent used.
Enantiomerically pure compounds of the formula II can be separated in a known manner (for example by preparation and separation of corresponding diastereoisomeric compounds) or prepared by stereoselective synthesis methods. Such separation processes and synthesis methods are described, for example in EP 247 971 and in DE 42 17 401.
Compounds of the formula III in which R1, R2, R3 and R4 have the meanings indicated above are accessible from the corresponding compounds of the formula IV 
in which R1, R2 and R3 have the meanings indicated above, by reaction with compounds of the formula R4-CO-Y in which R4 has the meanings indicated above and Y is a suitable leaving group, preferably a chlorine atom. For example, the benzoylation is carried out as in the following examples according to the Einhorn process, the Schotten-Baumann variant or as described in J. Chem. Soc. (C), 1971, 1805-1808.
Compounds of the formula R4-CO-Y are either known or can be prepared by reaction from the corresponding carboxylic acids R4-COOH in which R4 has the meaning indicated above in a familiar manner to the person skilled in the art.
The compounds R4-COOH in which R4 has the meanings indicated above are either known or can be obtained from alkyl 2-, 3- or 4-cyanobenzoates in a manner known to the person skilled in the art, e.g. by reaction with alkali metal azides and an ammonium halide (e.g. ammonium chloride) to give alkyl 2-, 3- or 4(1H- or 2H-tetrazol-5-yl)benzoates which are unsubstituted in the tetrazole moiety. Such a reaction is described, for example, in J. Med. Chem. 1993, 36, 3246. If desired, these intermediate compounds can be convertedxe2x80x94as described above for the 1H- or 2H-tetrazole compounds of the formula II or in the abovementioned literaturexe2x80x94by alkylation with compounds of the formula R6-X in the presence of a base, into alkyl R4-carboxylates in which R4 is a phenyl radical substituted by R5, R5 is a 1 H- or 2H-tetrazol-5-yl radical substituted by a radical R6 and R6 is not hydrogen, but has one of the other meanings mentioned for R6. By means of alkaline or acidic hydrolysis conditions familiar to the person skilled in the art, the alkyl R4-carboxylates are converted into the free carboxylic acids R4-COOH.
The preparation of cis/trans racemate mixtures and of pure cis racemates of compounds of the formula IV is described, for example, in U.S. Pat. 3,899,494, in DE-A 21 23 328 and in DE-A 16 95 782. Pure cis-enantiomers of the compounds of the formula IV can be obtained, for example, by the processes such as are described in EP 0 247 971 and in DE 42 17 401.
The substances according to the invention are isolated and purified in a manner known per se, for example by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as, for example, column chromatography on a suitable support material.
Salts are obtained by dissolving the free compound in a suitable solvent (e.g. a ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, an ether, such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added. The salts are obtained by filtering, reprecipitating, precipitating with a nonsolvent for the addition salt or by evaporating the solvent. Salts obtained can be converted into the free compounds, which can in turn be converted into salts, by alkalization or by acidification. In this manner, pharmacologically intolerable salts can be converted into pharmacologically tolerable salts.
The following examples serve to illustrate the invention in greater detail without restricting it. Further compounds of the formula I, whose preparation is not explicitly described, can also be prepared in an analagous manner or in a manner familiar per se to the person skilled in the art using customary process techniques.